. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-68. Epub 2011 Sep 21 PubMed.


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  1. At long last, these two papers from the Traynor and Rademakers groups resolve the mystery of the gene on chromosome 9 implicated in ALS and FTD. The authors identify massively expanded GGGGCC repeats in the non-coding region of a gene known as C9ORF72. Unfortunately, not much is known about this gene, but amazingly, these abnormal repeats not only result in ALS/FTLD, but the disease-causing effects of these repeats appear, at least in part, to work through accumulations of TDP-43 pathology. Thus, we have yet another genetic abnormality that results in ALS/FTLD by perturbing TDP-43 metabolism with attendant presumptive losses of TDP-43 nuclear functions or gains of toxic properties by aggregated TDP-43. Moreover, these genetic abnormalities were reported to be the most common cause of familial ALS/FTLD, and they also appear to account for a significant number of sporadic ALS/FTLD. These findings add further compelling evidence to the concept prompted by the discovery of TDP-43 pathology in ALS and FTLD that these are related disorders at either ends of clinical and pathological spectra that may also co-occur in the same patient (Neumann et al., 2006).

    What is startling is how multiple genetic and non-genetic triggers of ALS-FTLD share a common neuropathology, i.e., misfolded aggregates of TDP-43, and while it will be a challenge to resolve this enigma, this shared TDP-43 pathology may be an attractive target to focus on for ALS/FTLD drug discovery, regardless of the initiating genetic or environmental drivers of this neurodegenerative disease.


    . Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. PubMed.

    View all comments by John Trojanowski
  2. This is a very important finding, with implications for sporadic and familial ALS and FTD. The discovery in Rosa Rademakers' lab really hinged on following up apparently non-Mendelian inheritance of a microsatellite marker, something that many people would dismiss as lab error. Instead, by following the pattern to its conclusion, they identified the massive expansion that is the likely pathogenic variant in this case. This is science at its best. The fact that Bryan Traynor's group were also able to identify it independently using anomalies from Next Generation Sequencing results is also impressive. A striking feature of the discovery is just how much of ALS and FTD can be explained by this locus, with Traynor's group showing that nearly half of all Finnish familial cases, a fifth of all Finnish sporadic cases, and a third of European familial cases are due to this locus.

    Several questions immediately come to mind, only some with answers.

    1. How does this expansion lead to ALS? Preliminary findings suggest that there is either sequestration of RNA or a change in transcript expression ratios, or both. The protein product of C9ORF72 itself is uncharacterized, and funcbase does not provide an obvious explanation through its predictions.

    2. Why does the mutation lead to both sporadic and familial disease? Although we tend to think of familial disease as due to large-effect rare variants and sporadic disease as due to multiple, small-effect variants, this does not need to be the case. One explanation, suggested by Rademakers' group, is that the mutation occurs relatively frequently de novo because the haplotype somehow predisposes to this. However, one does not need to invoke this explanation (although it may well be true), since single, large-effect rare variants will frequently lead to sporadic disease (1), and in the ratio of familial to sporadic described here.

    3. Why does the expansion occur at all? Rademakers' group describe the intriguing result that the normal population with the risk haplotype have a larger average number of repeats than those with non-risk haplotypes, suggesting that the risk haplotype may make this region unstable in some way and therefore predisposed to such dramatic expansion.

    4. Is it always on the same haplotype? This remains unclear as the two papers disagree on this point.

    5. Can we develop a quick screening test? Both papers suggest that a method called repeat-primed PCR could be a quick screening method (2), although Rademakers' group also used Southern blotting, and Traynor's group fluorescent in-situ hybridization.

    The finding is another important genetic discovery for ALS and FTD, and adds to the growing list of genes contributing to these diseases.


    . Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Hum Hered. 2011;71(4):281-8. PubMed.

    . Qualitative assessment of FMR1 (CGG)n triplet repeat status in normal, intermediate, premutation, full mutation, and mosaic carriers in both sexes: implications for fragile X syndrome carrier and newborn screening. Genet Med. 2010 Mar;12(3):162-73. PubMed.

    View all comments by Ammar Al-Chalabi

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